Abstract

The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels
that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates
hypothalamic neuropeptide Y/agouti gene–related protein neurons and increases food intake and body weight. These findings
suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine
whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and
leptin were measured by radioimmunoassay in plasma samples drawn 38 times throughout a 24-h period in 10 healthy subjects
provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to
trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal
rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then
falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly
with 24-h integrated area under the curve values (r = 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h
profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r = 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays
a physiological role in meal initiation in humans.